product monograph verapamil hydrochloride injection usp 2

PRODUCT MONOGRAPH

PrVerapamil Hydrochloride Injection USP

2.5 mg/mL

2 mL Ampoules and Vials

Sterile Solution

Antiarrhythmic

Pfizer Canada ULC17300 Trans-Canada HighwayKirkland, QuébecH9J 2M5

Date of revision: May 18, 2021

Control Number: 247539

Product Monograph – PrVerapamil Hydrochloride Injection USP of 46

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 3

SUMMARY PRODUCT INFORMATION .................................................................................... 3INDICATIONS AND CLINICAL USE .......................................................................................... 3CONTRAINDICATIONS ............................................................................................................... 4WARNINGS AND PRECAUTIONS .............................................................................................. 4ADVERSE REACTIONS ............................................................................................................ 11DRUG INTERACTIONS ............................................................................................................ 14DOSAGE AND ADMINISTRATION ........................................................................................ 26OVERDOSAGE .......................................................................................................................... 28ACTION AND CLINICAL PHARMACOLOGY ....................................................................... 30STORAGE AND STABILITY .................................................................................................... 33DOSAGE FORMS, COMPOSITION AND PACKAGING ........................................................ 33

PART II: SCIENTIFIC INFORMATION .......................................................................................... 34

PHARMACEUTICAL INFORMATION .................................................................................... 34DETAILED PHARMACOLOGY ............................................................................................... 35TOXICOLOGY ........................................................................................................................... 36REFERENCES ............................................................................................................................ 39

PART III: CONSUMER INFORMATION ......................................................................................... 43


PrVerapamil Hydrochloride Injection USP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Administration Dosage Form/Strength All Non-medicinal Ingredients

Intravenous Solution for intravenousinjection, 2.5 mg/mL

sodium chloride, hydrochloric acid

and water for injection.

INDICATIONS AND CLINICAL USE

Verapamil Hydrochloride Injection USP is indicated for life-threatening cardiac arrhythmias under the following conditions:

Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong-Levine [L-G-L] syndromes). When clinically advisable, appropriate vagal manoeuvres (e.g. Valsalva manoeuvre) should be attempted prior to administration of verapamil hydrochloride.

Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff Parkinson-White [W-P-W] and Lown-Ganong-Levine [L-G-L] syndromes).

Because a small fraction (<1.0%) of patients treated with verapamil hydrochloride respond with life-threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation and accessory bypass tract, marked hypotension, or extreme bradycardia/asystole) (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS), the use of intravenous verapamil hydrochloride should be in a treatment setting with monitoring and resuscitation facilities, including DC cardioversion capability (see OVERDOSAGE). Cardioversion has been used safely and effectively after intravenous verapamil hydrochloride.

Geriatrics (≥65 years of age):Caution should be exercised when Verapamil Hydrochloride Injection USP is administered to elderly patients(see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (≥65 years of age)).

Pediatrics (< 18 years of age):Caution should be used when administering Verapamil Hydrochloride Injection USP to pediatricpatients.


CONTRAINDICATIONS

Verapamil Hydrochloride Injection USP is contraindicated in:

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGINGsection of the Product Monograph.

Complicated myocardial infarction (patients who have ventricular failure manifested by pulmonarycongestion).

Severe left ventricular dysfunction (see WARNINGS AND PRECAUTIONS, Cardiovascular, Heart Failure).

Cardiogenic shock. Severe hypotension. Second- or third-degree atrioventricular (A-V) block. Sick sinus syndrome (see WARNINGS AND PRECAUTIONS, Cardiovascular, Conduction

Disturbance). Marked bradycardia. Ventricular Tachycardia. (See WARNINGS AND PRECAUTIONS, Ventricular Tachycardia). Receiving intravenous beta-adrenergic blocking drugs (e.g. propanolol). Intravenous verapamil and

intravenous beta adrenergic blocking drugs should not be administered in close proximity to each other (i.e. within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction (see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS Table 2).

Patients with atrial flutter or atrial fibrillation in the presence of an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular arrhythmias including ventricular fibrillation and Torsade de pointes if verapamil hydrochloride is administered (see WARNINGS AND PRECAUTIONS, Cardiovascular, Accessory Bypass Tract).

Concomitant use of ivabradine (see DRUG INTERACTIONS). Patients taking flibanserin (see WARNINGS AND PRECAUTIONS, Cardiovascular,

Hypotension). Women who are breast-feeding (see WARNINGS AND PRECAUTIONS, Special Populations,

Nursing Women).

WARNINGS AND PRECAUTIONS

Verapamil Hydrochloride Injection USP should be given as a slow intravenous injection over at least a two-minute period of time and longer (at least three minutes) if the patient is 65 years of age or older(see DOSAGE AND ADMINISTRATION).

Because a small fraction (<1%) of patients treated with verapamil hydrochloride respond with life-threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation and accessory bypass tract, marked hypotension, or extreme bradycardia/asystole (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS), the use of Verapamil Hydrochloride Injection USP should be in a treatment setting with monitoring and resuscitation facilities, including DC-cardioversion capability (see OVERDOSAGE).


General

In patients with angina or arrhythmias using antihypertensive drugs, the additional hypotensive effect of Verapamil Hydrochloride Injection USP should be taken into consideration.

Verapamil hydrochloride does not alter total serum calcium levels. However, one report suggested that calciumlevels above the normal range may decrease the therapeutic effect of verapamil hydrochloride.

Carcinogenesis and Mutagenesis

There was no evidence of a carcinogenic effect when verapamil hydrochloride was administered orally (diet)to male and female rats at doses up to 112.2 and 102.5 mg/kg/day, respectively, for 24 months. These doses correspond to approximately 2.3 and 2 times human exposure based on body surface area, respectively.

In vitro mutagenicity tests showed that verapamil did not have mutagenic properties in five different strains ofSalmonella typhimurium, nor in studies on chromosomal aberrations and sister chromatid exchanges (SCE) inhuman lymphocytes, nor in the hypoxanthine guanine phosphoribosyltransferase (HGPRT)-test with V-79Chinese hamster cells, and also not in the cell transformation assay with Syrian hamster embryo cells. Inaddition, verapamil did not show any SCE-inducing activity in vivo (Chinese hamster) (see TOXICOLOGY, Carcinogenicity and Mutagenicity).

Cardiovascular

Heart Failure

Because of the drug's negative inotropic effect, verapamil hydrochloride should not be used in patients with poorly compensated congestive heart failure. Continuous monitoring is mandatory when intravenousverapamil hydrochloride is used in digitalized patients.

Heart failure patients with ejection fraction higher than 40% should be treated with adequate doses of digoxinand/or diuretics before starting Verapamil Hydrochloride Injection USP treatment.

If verapamil is administered concomitantly with digoxin, reduce digoxin dosage (see DRUG INTERACTIONS, Table 2). The use of verapamil hydrochloride in the treatment of hypertension is not recommended in patientswith heart failure caused by systolic dysfunction.

Hypotension

Severe hypotension has occasionally occurred following intravenous administration of the drug. On rare occasions, this has been followed by loss of consciousness. If severe hypotension develops, verapamil hydrochloride should be promptly discontinued and vasoconstrictor substances started, as described in OVERDOSAGE.

Intravenous verapamil hydrochloride often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic, but may result in dizziness. Intravenous administration of calcium chloride, or calcium gluconate prior to intravenous administration of verapamil hydrochloride may prevent this hemodynamic response (see OVERDOSAGE).


Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension.

Use of a moderate CYP3A4 inhibitor such as verapamil with flibanserin significantly increases flibanserin

concentrations, which can lead to severe hypotension and syncope (see CONTRAINDICATIONS).Discontinue Verapamil Hydrochloride Injection USP at least 2 weeks prior to starting flibanserin. Do notadminister Verapamil Hydrochloride Injection USP within 2 days of discontinuing flibanserin.

In patients using antihypertensive drugs, the additional hypotensive effect of verapamil hydrochloride shouldbe taken into consideration.

Conduction Disturbance

Verapamil hydrochloride affects the A-V and sinoatrial (S-A) nodes. Verapamil hydrochloride slows conduction across the A-V node. Verapamil hydrochloride should be used with caution in the presence of firstdegree A-V block. Patients with first degree A-V block may progress to second or third-degree A-V block; orunifascicular, bifascicular or trifascicular bundle–branch block; they require a reduction in the dose or discontinuation of Verapamil Hydrochloride Injection USP, and the institution of appropriate therapydepending upon the patient’s clinical condition (see OVERDOSAGE).

Verapamil hydrochloride causes dose-related suppression of the S-A node and rarely may produce second orthird degree A-V block, bradycardia and in extreme cases, asystole. In some patients, sinus bradycardia mayoccur, especially in patients with a sick sinus syndrome (S-A nodal disease), which is more common in olderpatients (see CONTRAINDICATIONS).

Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to A-V nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see ADVERSE REACTIONS and OVERDOSAGE).

Bradycardia

The total incidence of bradycardia (ventricular rate less than 50 beats/minute) was 1.4% in controlled studies.

Ventricular tachycardia

Administration of intravenous verapamil hydrochloride to patients with wide-complex ventricular tachycardia (QRS > 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pre-therapy diagnosis and differentiation from wide-complex supraventricular tachycardia (based on a12 lead ECG) is imperative in the emergency room setting.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine)

Intravenous administration of verapamil hydrochloride may precipitate ventricular fibrillation. Patients with atrial flutter/fibrillation and an accessory AV pathway (e.g. Wolff-Parkinson-White or Lown-Ganong-Levine syndromes) are at risk of developing ventricular arrhythmias including ventricular fibrillation and Torsade de pointes if verapamil hydrochloride is administered. They may develop increased antegrade conduction across the aberrant pathway bypassing the AV node, producing a very rapid ventricular response


after receiving verapamil hydrochloride or digitalis. This has been reported in approximately 1% of the patients treated in controlled double-blind trials. The use of verapamil hydrochloride in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC cardioversion. Cardioversion has been used safely and effectively after intravenous verapamil hydrochloride (see OVERDOSAGE).

Concomitant Use with Antiarrhythmics or Beta-Blockers

On rare occasions, the concomitant administration of intravenous beta-blockers and intravenous verapamil hydrochloride has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction. Concomitant use of verapamil hydrochloride withantiarrhythmics or beta-blockers may cause mutual potentiation of cardiovascular effects (higher-grade AVblock, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension).Asymptomatic bradycardia (< 36 beats/minute) with a wandering atrial pacemaker has been observed in apatient receiving concomitant timolol (a beta- adrenergic blocker) eye drops and oral verapamilhydrochloride (see DRUG INTERACTIONS, Table 2). This myocardial depressant effect (independent ofchanges in heart rate) can be significant in patients with impaired left ventricular performance. Accordingly,intravenous verapamil hydrochloride and intravenous beta adrenergic blocking drugs should not beadministered in close proximity to each other (i.e. within a few hours).

Concomitant Use with Lidocaine

Two deaths have been reported in patients receiving both verapamil hydrochloride and lidocaineintravenously.

Concomitant Use with Procainamide

Intravenous verapamil hydrochloride has been administered to a small number of patients receiving oralprocainamide without the occurrence of serious adverse effects.

Concomitant Use with HMG-CoA Reductase Inhibitors (“Statins”)

Concomitant use of verapamil hydrochloride and HMG-CoA reductase inhibitors may require dosage adjustments. see (DRUG INTERACTIONS, Table 2).

Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy who received oral therapy with verapamil hydrochloride atdoses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonaryedema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction.Eight other patients had pulmonary edema and/or severe hypotension, abnormally high (greater than 20 mmHg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most ofthese patients. Concomitant administration of quinidine (see DRUG INTERACTIONS) preceded the severehypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in11% of the patients, second-degree A-V block in 4%, and sinus arrest in 2%. It must be appreciated that thisgroup of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dosereduction, but in some cases, verapamil hydrochloride use had to be discontinued.

Premature Ventricular ContractionsDuring conversion to normal sinus rhythm, or marked reduction in ventricular rate, a few benign complexes


of unusual appearance (sometimes resembling premature ventricular contractions) may be seen aftertreatment with verapamil hydrochloride. Similar complexes are seen during spontaneous conversion ofsupraventricular tachycardias after DC-cardioversion and other pharmacologic therapy. These complexesappear to have no clinical significance.

Sick Sinus SyndromePrecaution should be taken when treating any supraventricular arrhythmia on an emergency basis as it may becaused by an undiagnosed Sick Sinus Syndrome (see CONTRAINDICATIONS).

Hepatic/Biliary/Pancreatic

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubinhave been reported. Several published cases of hepatocellular injury produced by verapamil hydrochloridehave been proven by rechallenge. Clinical symptoms of malaise, fever, and/or right upper quadrant pain, in

addition to elevation of serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvictransaminase (SGPT) and alkaline phosphatase have been reported. Periodic monitoring of liver function inpatients receiving verapamil hydrochloride is therefore prudent.

Hepatic Insufficiency

Because verapamil hydrochloride is extensively metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function, since the elimination half-life of verapamilhydrochloride in these patients is prolonged 4-fold (from 3.7 to 14.2 hours). A decreased dosage should be used in patients with hepatic insufficiency and careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect should be carried out (see ACTION ANDCLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).Neurologic

Neuromuscular Transmission Disorders

Due to verapamil hydrochloride’s neuromuscular blocking action, verapamil hydrochloride should be used with

caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis,Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy). It has been reported that verapamil hydrochloride decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil hydrochloride prolongs recovery from the neuromuscular blocking agent vecuronium.

The decision to administer verapamil hydrochloride should be based on the physician’s assessment of the riskand benefit to the patient. It may be necessary to decrease the dosage of verapamil hydrochloride when it is administered to patients with attenuated neuromuscular transmission. Ventilation support should be available if required (see DRUG INTERACTIONS, Drug-Drug Interactions, Use in Patients with Attenuated (Decreased) Neuromuscular Transmission).

Intravenous verapamil hydrochloride has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed.


Ophthalmologic

Atypical lens changes and cataracts were observed in beagle dog studies at high doses. This has beenconcluded to be species-specific for the beagle dog. (These ophthalmological changes were not seen in asecond study.) No similar changes have been observed in long-term prospective human ophthalmologicaltrials.

Renal

Renal Insufficiency

About 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the urine. Inone study in healthy volunteers, the total body clearance after intravenous administration of verapamilhydrochloride was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil hydrochloride in patientswith renal disease is decreased.

Therefore, until further data are available, Verapamil Hydrochloride Injection USP should be used with caution in patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect (see DOSAGE ANDADMINISTRATION).

Verapamil hydrochloride is not removed by hemodialysis.

Special Populations

Pregnant Women

There are no adequate and well-controlled study data in pregnant women. Verapamil hydrochloride crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil hydrochloride is notrecommended for use in pregnant women unless the potential benefits outweigh potential risks to mother andfetus.

Teratology and reproduction studies have been performed in rabbits and rats with oral verapamil administered at doses up to 15 mg/kg/day and 60 mg/kg/day (human equivalent doses of 288 mg/day and 576 mg/day, respectively, assuming human body weight at 60 kg) respectively, and have revealed noevidence of teratogenicity or impaired fertility. In the rat, however, a dose of 60 mg/kg/day (human equivalent dose of 576 mg/day, similar to the maximum clinical dose of 480 mg/day) was embryocidal andretarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflectedby reduced food consumption and weight gains of dams). This oral dose has also been shown to causehypotension in rats.

Labour and Delivery

It is not known whether the use of verapamil hydrochloride during labour or delivery has immediate ordelayed adverse effects on the fetus, or whether it prolongs the duration of labour or increases the need forforceps delivery or other obstetric intervention.


Nursing Women

Verapamil hydrochloride is excreted in human breast milk. Because of the potential for adverse reactions in

nursing infants from verapamil hydrochloride, nursing should be discontinued while Verapamil hydrochloride is administered.

Pediatrics (< 18 years of age)

Use in Children

Controlled studies with verapamil hydrochloride have not been conducted in pediatric patients. However, uncontrolled experience in more than 250 children (about 50% under 12 months of age and about 25% newborn) indicates that the results of treatment are similar to those in adults. However, in rare instances, severe hemodynamic side effects, some of them fatal, have occurred following the intravenous administration of verapamil hydrochloride in neonates and infants. Caution should therefore be used when administering verapamil hydrochloride to this group of pediatric patients.

Geriatrics (<65 years of age)

Caution should be exercised when verapamil hydrochloride is administered to elderly patients (≥65 years) especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency(see DOSAGE AND ADMINISTRATION). The incidence of adverse reactions is approximately 4%

higher in the elderly. The adverse reactions occurring more frequently include dizziness and constipation.Serious adverse events associated with heart block have occurred in the elderly.

Monitoring and Laboratory Tests

Patients should be monitored by measuring the blood pressure response.

Concomitant Use with Beta-Blockers

The use of intravenous verapamil hydrochloride with beta-blockers and cardiac depressant drugs can produce a reduction of myocardial contractility. This myocardial depressant effect (independent of changes in heart rate) can be significant in patients with impaired left ventricular performance.

On rare occasions the concomitant administration of intravenous beta-blockers and intravenous verapamil hydrochloride has resulted in severe adverse effects, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction (see CONTRAINDICATIONS). Accordingly,intravenous verapamil hydrochloride and intravenous beta adrenergic blocking drugs should not beadministered in close proximity to each other (i.e. within a few hours).

Elevated Liver Enzymes

Periodic monitoring of liver function in patients receiving verapamil hydrochloride is prudent.

Hepatic Insufficiency


Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologiceffect should be carried out.

Renal Insufficiency

Patients with renal insufficiency should be carefully monitored for abnormal prolongation of the PRinterval or other signs of excessive pharmacologic effect.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In 4,826 patients treated with verapamil hydrochloride immediate release tablets for arrhythmias, angina orhypertension, the overall adverse reaction rate in these patients was 37.1% and the dropout rate was 10.2%.The majority of these patients were seriously ill and treated under emergency drug regulations.

In controlled pivotal studies with 128 patients treated with verapamil hydrochloride sustained-release tabletsfor hypertension, the overall adverse reaction rate was 21.7% and the dropout rate was 3.9%.

The most common adverse reactions were: constipation (7.3%), dizziness (3.2%), and nausea (2.7%). In

hypertension studies, constipation occurred in 18.5% of patients on verapamil hydrochloride immediaterelease tablets and 4.7% of patients on verapamil hydrochloride sustained-release tablets.

The most serious adverse reactions reported with verapamil hydrochloride are heart failure (1.8%),hypotension (2.5%), A-V block (1.2%) and rapid ventricular response (see WARNINGS ANDPRECAUTIONS).

The incidence of all adverse reactions, including those seen with both the oral and intravenous use of verapamil hydrochloride, is about 10.6%, with 6.7% associated with oral administration.

Approximately 1.4% of these patients required discontinuation of the drug because of side effects. The most common adverse effect seen with oral verapamil hydrochloride is constipation, while hypotension and bradycardia are more common with its intravenous use.

In rare cases of hypersensitive patients, broncholaryngeal spasm accompanied by itch and urticaria have been reported.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty. One case of anaphylactic shock following intravenous verapamil hydrochloride has also been reported.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed inthe clinical trials may not reflect the rates observed in practice and should not be compared to the rates inthe clinical trials of another drug. Adverse drug reaction information from clinical trials is useful foridentifying drug-related adverse events and for approximating rates.

Intravenous verapamil hydrochloride:


The following adverse reactions were reported with intravenous verapamil hydrochloride use in controlledclinical trials involving 324 patients:

Cardiovascular: Symptomatic hypotension (1.5%), bradycardia (1.2%), severe tachycardia (1%). Theworldwide experience in open clinical trials in more than 7900 patients was similar.

Central Nervous System: Dizziness (1.2%), headache (1.2%). Occasional cases of seizures during verapamilhydrochloride injection have been reported.

Gastrointestinal: Nausea (0.9%), abdominal discomfort (0.6%).

Respiratory: In rare cases of hypersensitive patients, broncholaryngeal spasm accompanied by itch andurticaria have been reported.

Miscellaneous: The following reactions were reported at low frequency:

Skin reactions, exanthema, urticaria, pruritus, muscular cramps, arthralgia, emotional depression, confusion,rotary nystagmus, diplopia, impaired vision, sleepiness, insomnia, muscle fatigue, diaphoresis, painful coldnessand numbness in the extremities, paresthesia, hyperkinesia, impotence.

Adverse Drug Reactions Associated with the Use of Oral Verapamil

The following adverse reactions divided by body system have been reported in clinical trials or marketing

experience. When incidences are shown, they are calculated based on the 4,954 (4,826 + 128) patient base.

Table 1. Adverse Reactions Reported in Clinical Trials

Verapamil Hydrochloride

(N = 4,954)

Vascular Disorders

Hypotension 2.5%

Cardiac Disorders

Edema 2.1%

CHF/Pulmonary Edema 1.9%

Bradycardia 1.4%

A-V Block

Total (1º, 2º, 3º)

2º and 3º

1.2%

0.8%

Nervous System Disorders

Dizziness 3.2%

Headache 2.2%

General Disorders and Administration Site Conditions


Fatigue 1.7%

Gastrointestinal Disorders

Constipation 7.3%

Nausea 2.7%

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea 1.4%

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

The following reactions were reported in 1.0% or less of patients in clinical trials:

Cardiac Disorders: angina pectoris, atrioventricular dissociation, cardiac failure, chestpain, claudication, development of rhythm disturbances, myocardialinfarction, painful coldness and numbness of extremities,palpitations, syncope, severe tachycardia, ventricular dysrhythmias

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blurred vision, diplopia

Nervous System Disorders: cerebrovascular accident, confusion, equilibrium disorders,excitation, extrapyramidal disorders, hyperkinesia, paresthesia,rotary nystagmus, shakiness, somnolence, tremor

Gastrointestinal Disorders: abdominal discomfort, diarrhea, dry mouth, gastrointestinaldistress, gingival hyperplasia, vomiting

Musculoskeletal and ConnectiveTissue Disorders:

arthralgia, muscle cramps, muscle fatigue

Psychiatric Disorders: depression, insomnia, psychotic symptoms

Renal and Urinary Disorders: increased frequency of urination

Respiratory, Thoracic and Mediastinal Disorders:

bronchospasm, dyspnea

Reproductive System and Breast Disorders:

erectile dysfunction, gynecomastia, oligomenorrhea, spotty menstruation

Skin and Subcutaneous System Disorders:

alopecia, ecchymosis or bruising, erythema multiforme, exanthema, hyperkeratosis, macules, pruritus, purpura, rash, Stevens-Johnson syndrome, sweating, urticaria

Vascular Disorders: flushing

Isolated cases of renal failure and angioedema have been reported. Angioedema may beaccompanied by breathing difficulty.


In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillationor flutter, ventricular rates below 50 at rest occurred in 15% of patients and asymptomatic hypotensionoccurred in 5% of patients.

Abnormal Hematologic and Clinical Chemistry Findings

Hepatotoxicity with elevated enzymes (SGOT, SGPT, alkaline phosphatase) and bilirubin levels, jaundiceand associated symptoms of hepatitis with cholestasis have been reported (see WARNINGS ANDPRECAUTIONS). Elevated prolactin levels have also been reported.

Post-Market Adverse Drug Reactions

The following adverse events have been reported with verapamil hydrochloride from post- marketingsurveillance or Phase 4 clinical trials.

Cardiac Disorders: asystole, sinus arrest, sinus bradycardia

Ear and Labyrinth Disorders: tinnitus

Gastrointestinal Disorders: abdominal pain, ileus

General Disorders and Administration SiteConditions:

edema peripheral

Immune System Disorders: hypersensitivity

Metabolism and Nutrition Disorders:

Musculoskeletal and ConnectiveTissue Disorders:

hyperkalaemia

muscle weakness, myalgia

Nervous System Disorders: paralysis (tetraparesis)1, seizure

Skin and Subcutaneous System Disorders:

hyperhidrosis, itching, rash maculopapular

Reproductive System and Breast Disorders:

galactorrhea

1There has been a single post-marketing report of paralysis (tetraparesis) associated with the combined use ofverapamil hydrochloride and colchicine. This may have been caused by colchicine crossing the blood-brainbarrier due to CYP3A4 and P-glycoprotein (P-gp) inhibition by verapamil hydrochloride. See (DRUGINTERACTIONS).

DRUG INTERACTIONS

Drug-Drug Interactions


As with all drugs, care should be exercised when treating patients with multiple medications. Verapamil hydrochloride undergoes biotransformation by the CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 isoenzymes of the cytochrome P450 system. Verapamil hydrochloride has also been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Co-administration of verapamil hydrochloride with other drugs which follow the same route of biotransformation or are inhibitors or inducers of these enzymes may result in altered bioavailability of verapamil hydrochloride or these drugs. Co-administration of verapamil and a drug primarily metabolized by CYP3A4 or being a P-gp substrate may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered verapamil hydrochloride to maintain optimum therapeutic blood levels.

The following table provides a list of potential drug interactions:

Table 2. Potential Drug Interactions Associated with Verapamil Hydrochloride

Concomitant Drug Class: Drug Name

Ref Effect Clinical Comment

Alpha-Blockers

Prazosin T ↑ prazosin Cmax (~40%)with no effect on t½

Concomitant use of verapamil hydrochloride and alpha-adrenoceptorblockers may result in excessive fall in blood pressure in some. patients as observed in one study following the concomitant administration of verapamil hydrochloride and prazosin.

Terazosin CT ↑ terazosin AUC (~24%) and Cmax (~25%)

Antiarrhythmics

Amiodarone ↑ bradycardia Verapamil hydrochloride should beused with caution in patients receivingamiodarone because of the possiblepotentiation of bradycardia, sinus arrest, and AV block.

Disopyramide T Until data on possible interactionsbetween verapamil hydrochloride anddisopyramide are obtained, disopyramide should not be administered within 48 hours beforeor 24 hours after verapamil hydrochloride administration.




Flecainide CT C Minimal effect on flecainide plasma clearance (< ~10%); no effect on verapamilplasma clearance.

The concomitant administration offlecainide and verapamil hydrochloride may have additiveeffects on myocardial contractility, A-V conduction, and repolarisation. Mayalso have negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine CT ↓ oral quinidine clearance (~35%)

In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamilhydrochloride and quinidine resulted in significant hypotension and may resultin pulmonary edema. Until further data are obtained, combined therapy ofverapamil hydrochloride and quinidinein patients with hypertrophic cardiomyopathy should be avoided.

The electrophysiological effects of quinidine and verapamil hydrochloride on A-V conduction were studied in 8 patients. Verapamilhydrochloride significantly counteracted the effects of quinidineon A-V conduction. There has been areport of increased quinidine levelsduring verapamil hydrochloride therapy.




Anti-asthmatics

Theophylline C ↓ oral and systemicclearance of theophylline by ~20%. Reduction of clearance was lessened insmokers (~11%).

Caution should be exercised when co-administering theophylline andverapamil hydrochloride.

Anticoagulants

Dabigatran CT ↑ dabigatran (Cmax up to

90%) and AUC (up to 70%)

To minimize potential interaction, dabigatran should be given at least 2 hours before verapamil.

Other direct oralanticoagulants(DOACs; e.g.

rivaroxaban, apixaban,and edoxaban)

C Increased absorption of DOACs since they are P‐gp substrates and, if applicable, also reduced elimination of

DOACs which are metabolized by CYP3A4, may increase the systemic bioavailability of DOACs.

Some data suggest a possible increase ofthe risk of bleeding, especially inpatients with further risk factors. Thedose of DOAC with verapamil may needto be reduced (see DOAC label fordosing instructions).

Anticonvulsants / Anti-epileptics

Carbamazepine C ↑ carbamazepine AUC(~46%) in refractorypartial epilepsy patients

Concomitant oral use may potentiate the effects of carbamazepine neurotoxicity. Symptoms include nausea, diplopia, headache, ataxia or dizziness. Patientsreceiving these drugs concurrentlyshould be monitored for a potential druginteractions and dose adjustment ofcarbamazepine and/or verapamil may benecessary.

Phenytoin C ↓ verapamil plasma concentrations

Verapamil plasma concentration maynot achieve its therapeutic level when itis administrated concomitantly withphenytoin.


Concomitant Drug

Class: Drug Name


Antidepressants

Imipramine T ↑ imipramine AUC(~15%). No effect on level of active metabolitedesipramine.

As with all antihypertensive agents, there is an elevated risk of orthostatic hypotension when combining verapamil hydrochloride with major tranquilizers or tricyclic antidepressants, such as imipramine.

Antidiabetics

Glibenclamide (glyburide)

T ↑ glibenclamide Cmax(~28%), AUC (~26%)

Anti-gout

Colchicine CT ↑ colchicine AUC (~ 2.0-fold) and Cmax (~1.3-fold)

Colchicine is a substrate for both CYP3A and the efflux transporter P-gp. Verapamil hydrochloride is known to inhibit CYP3A and P-gp. When verapamil hydrochloride and colchicineare administered together, inhibition of P-gp and/or CYP3A by verapamilhydrochloride may lead to increased exposure to colchicine. Combined use isnot recommended.

Antihypertensive Agents

ACE inhibitors,vasodilators, diuretics.

C ↓ blood pressure Verapamil hydrochloride administered concomitantly with antihypertensiveagents such as vasodilators, ACEinhibitors, and diuretics may have an additive effect on lowering blood pressure. In patients with angina orarrhythmias using antihypertensive drugs, this additional hypotensive effect should be taken into consideration.

Anti-Infectives

Clarithromycin C Possible ↑ in verapamilwhen used in combination with clarithromycin

Severe hypotension and bradycardia have been observed in patients receiving concurrent clarithromycin.


Concomitant Drug

Class: Drug Name


Erythromycin C Possible ↑ in verapamilwhen used in combination with erythromycin

Rifampicin T ↓ verapamil AUC (~97%),

Cmax (~94%) oral

bioavailability (~92%)

Blood pressure lowering effect of verapamil hydrochloride may be reduced when used concomitantly withrifampicin.

Telithromycin T Possible ↑ in verapamilwhen used in combination with telithromycin

Antimanic Agents

Lithium T Increased sensitivity to the effects oflithium (neurotoxicity) has been reported during concomitant verapamilhydrochloride-lithium therapy.

Lithium based drugs should be administered with caution, and frequent monitoring of serum lithium levels isrecommended. If a diuretic is also used, the risk of lithium toxicity may be further increased.

Antineoplastics

Doxorubicin T ↑ doxorubicin AUC (104%) and Cmax (61%) with oral

verapamil administration in patients with small cell lung cancer.

In patients with advanced neoplasm, intravenous verapamil administration did not change

significantly doxorubicin PK.

Verapamil hydrochloride inhibits P-glycoprotein (P-gp)-mediated transport of anti-neoplastic agents out of tumour cells, resulting in their decreased metabolic clearance. Dosage adjustments of anti-neoplastic agents should be considered when verapamil hydrochloride is administered concomitantly.


Concomitant Drug

Class: Drug Name


Barbiturates

Phenobarbital T ↑ oral verapamil clearance (~5-fold)

Benzodiazepines and Other Anxiolytics

Buspirone T ↑ buspirone AUC, Cmax by

~3.4-fold

Verapamil significantly increases peakplasma levels of buspirone and midazolam. Special care (close medicalattention and/or dose adjustment) should be taken when prescribing short-actingbenzodiazepines metabolized by CYP3A4in patients using Verapamil HCl

Midazolam T

C

↑ midazolam AUC (~3-fold) and, Cmax (~2-fold)

Beta-Blockers

Atenolol T

C

A variable increase in atenolol plasma concentration at steady state has been reported in patients with angina pectoris.

Concomitant therapy may result in additive negative effects on heart rate,atrioventricular conduction and/or cardiac contractility (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).Verapamil hydrochloride must not be combined with beta-blockers for thetreatment of hypertension.

Metoprolol T

C

↑ metoprolol AUC (~32.5%) and Cmax(~41%) in patients with angina pectoris

Propranolol T

C ↑ propanolol AUC (~65%), Cmax (~94%) in patients with angina pectoris

Timolol T

C

Asymptomatic bradycardia (< 36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eye drops and oralverapamil hydrochloride.


Concomitant Drug

Class: Drug Name


Cardiac Glycosides

Digoxin C ↑ digoxin levels ~50-75% during the first week of therapy

↑ digoxin AUC (~32%), Cmax

(~98%) in hepatic cirrhosis patients

↑ digoxin Cmax (~44%),

↑ digoxin C12h (~53%), ↑

Css (~44%) and ↑ AUC

(~50%) in healthy subjects

Concurrent use with Digoxin may have additive effects on AV nodal conduction which could result in complete heart block.

The increase in digoxin levels can resultin digoxin toxicity. Maintenance digoxin doses should be reduced when verapamil hydrochloride is administered, and the patient should be carefully monitored to avoid over- or under-digitalization. Whenever overdigitalization is suspected, the dailydose of digoxin should be reduced or temporarily discontinued. Upon discontinuation of verapamilhydrochloride, the patient should be reassessed to avoid underdigitalization. (see WARNINGS AND PRECAUTIONS).

Cardiac If Current Inhibitor

Ivabradine CT Given its moderate CYP3A4 inhibitory effect, verapamil (120 mg b.i.d.), when co-administered with ivabradine, increases the ivabradineplasmaAUC by 2- to 3- fold.

Both verapamil and ivabradine are heart rate lowering substances andhence, co- administration could lead to an exacerbatedreduction in patient’s heartrate.

Given the increase in ivabradine exposure and additive heart rate lowering effect, the concomitant use of verapamil hydrochloride with ivabradine is contraindicated (see CONTRAINDICATIONS).

Diuretics

T Concomitant use with diuretics may cause a potentiation of the hypotensive effect.


Concomitant Drug

Class: Drug Name


Gynecological

Flibanserin T Use of a moderate CYP3A4inhibitor such as verapamilwith flibanserin significantlyincreases flibanserinconcentrations, which canlead to severe hypotensionand syncope (seeCONTRAINDICATIONSand WARNINGS ANDPRECAUTIONS,Cardiovascular,Hypotension).

Concomitant use of verapamil HCl andflibanserin is contraindicated.Discontinue verapamil HCl at least 2weeks prior to starting flibanserin. Do not administer verapamil HCl within 2days of discontinuing flibanserin. (seeCONTRAINDICATIONS andWARNINGSAND PRECAUTIONS, Cardiovascular,Hypotension).

H2-Receptor Antagonists

Cimetidine T In healthy subjects, ↑ AUCof R-(~25%) and S-(~40%) verapamil with corresponding ↓ in R- and S-verapamil clearance

HIV Antiviral Agents

HIV Antiviral Agents T Due to the metabolic inhibitory potentialof some of the HIV antiviral agents, suchas ritonavir, plasma concentrations ofverapamil hydrochloride may increase.Caution should be used or the dose of verapamil hydrochloride may be decreased.


Concomitant DrugClass: Drug Name


Immunosuppressive Agents

Cyclosporine T ↑ cyclosporine AUC, Css,

Cmax by 45% in renal

transplant patients

The co-administration of verapamil and immunosuppressive agents both known substrates and inhibitors for CYP 3A4 may increase the plasma levels of these drugs. Dose adjustment should be considered when these drugs are concomitantly administered, which may be assessed by blood levels, blood pressure monitoring and clinical monitoring of other patient symptoms.

Everolimus T Everolimus: ↑ AUC (~3.5-fold) and ↑ Cmax (~2.3-fold)

Verapamil: ↑ Ctrough(~2.3-fold)

Sirolimus T

C

Sirolimus ↑ AUC (~2.2-fold); S-verapamil ↑ AUC(~1.5-fold)

Tacrolimus T Possible ↑ tacrolimus levels

Lipid Metabolism Regulators (HMG-CoA Reductase Inhibitors)

Atorvastatin T Possible ↑ atorvastatin levels

↑ verapamil AUC by~43%

Treatment with HMG-CoA reductase inhibitors (e.g. atorvastatin, simvastatin or lovastatin) in a patient takingverapamil hydrochloride should be started at the lowest possible dose and titrated upwards. If verapamilhydrochloride treatment is to be added to patients already taking an HMG- CoAreductase inhibitor (e.g. atorvastatin, simvastatin or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.The maximum daily dose of simvastatin and lovastatin coadministered with verapamil hydrochloride should not exceed 10 and 20 mg, respectively.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and areless likely to interact with verapamil hydrochloride.

Lovastatin C Possible ↑ lovastatin levels

↑ verapamil AUC (by~63%) and Cmax by

(~32%)

Simvastatin C ↑ simvastatin AUC (~2.6-fold), Cmax (~4.6 fold) in

healthy subject


Concomitant DrugClass: Drug Name


Neuromuscular Blocking Agents

NeuromuscularBlocking Agents

e.g. atracurium

CT C Clinical data and animal studies suggest that verapamil hydrochloride may potentiate the activity of neuromuscularblocking agents (curare-like anddepolarizing). It may, therefore, benecessary to decrease the dose of verapamil hydrochloride and/or the doseof the neuromuscular blocking agentwhen the drugs are used concomitantly.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs)

Non-SteroidalAnti-Inflammatory Agents (NSAIDs)

e.g. Acetylsalicylic acid

T Potential adverse reactions in terms of bleeding due to synergistic antiplateleteffects of acetylsalicylic acid and verapamil hydrochloride should be taken into consideration in patients taking thetwo agents concomitantly.

Serotonin Receptor Agonists

Almotriptan T ↑ almotriptan AUC (~20%)

↑ Cmax (~24%)

Uricosurics

Sulfinpyrazone T ↑ verapamil oral clearance (~3-fold)

↓ bioavailability (~60%)

The blood pressure lowering effect of verapamil hydrochloride may be reduced

Vasodilators

Vasodilators T Concomitant use with vasodilators maycause a potentiation of the hypotensive effect.


Concomitant Drug

Class: Drug Name


Others

Dantrolene Two animal studies suggest concomitantIV use of verapamil and dantrolenesodium may result in cardiovascularcollapse.There has also been one report ofhyperkalemia and myocardial depression following thecoadministration of oral verapamil hydrochloride and intravenousdantrolene.

The combination of intravenousdantrolene sodium and calcium channelblockers, such as verapamil, should not beused during the reversal of a malignanthyperthermia crisis.

Inhalation anesthetics T ↑depression of cardiaccontractility

Animal experiments have shown thatinhalation anesthetics depresscardiovascular activity by decreasing theinward movement of calcium ions. Whenused concomitantly, inhalation anestheticsand calcium antagonists (such asverapamil hydrochloride) should be titrated carefully to avoid excessivecardiovascular depression

Plasma bound drugs As verapamil is highly bound to plasmaproteins, it should be administered withcaution to patients receiving other highlyprotein bound drugs

Legend: C= Case Study; CT = Clinical Trial; T = Theoretical

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil hydrochloride decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil hydrochloride prolongs recovery from the neuromuscular blocking agent vecuronium. Accordingly, it may be necessary to decrease the dosage of verapamil hydrochloride when it is administered to patients with attenuated neuromuscular transmission (see WARNINGS AND PRECAUTIONS: Neurologic: Neuromuscular Transmission Disorders).


Drug-Food Interactions

In healthy volunteers, multiple high doses of grapefruit juice increased the AUC for R-verapamil and S-verapamil by up to 49 and 37%, respectively. The increase in Cmax for R-verapamil and S- verapamil

were up to 75 and 51%, respectively. Elimination half-life and renal clearance of both S- and R-verapamilwere not affected. Grapefruit juice should therefore not be ingested with verapamil.

Drug-Herb Interactions

In healthy volunteers, multiple doses of St John’s Wort decreased the AUC for R- and S-verapamilhydrochloride by 78 and 80%, respectively, with similar decreases in Cmax.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been evaluated.

Drug-Lifestyle Interactions

Verapamil hydrochloride may increase blood alcohol (ethanol) concentrations and prolong its effects.

Depending on the individual response, verapamil hydrochloride may affect the ability to react to the point ofimpairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This appliesall the more at the start of treatment, when the dose is raised, when switching from another drug and inconjunction with alcohol.

DOSAGE AND ADMINISTRATION

Verapamil Hydrochloride Injection USP should be administered as a slow intravenous injection over at least a two minute period of time (longer if the patient is 65 years of age or older). It should be administered in hospital, where coronary care facilities are available and continuouselectrocardiographic and blood pressure monitoring are performed and resuscitation facilities (including D.C. cardioversion capability) is available.

Verapamil Hydrochloride Injection USP should be inspected visually for particulate matter and discolouration prior to administration. Use only if solution is clear. Any unused portion should be discarded immediately.

Admixing verapamil hydrochloride with sodium lactate in polyvinyl chloride containers, albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided. Verapamil hydrochloride will precipitate in any solution with a pH above 6.

The dosage of verapamil hydrochloride should be individualized for each patient based on response and tolerance. In some cases doses smaller than those recommended appear sufficient. Injection should only be continued to the point of therapeutic effect, at which point the intravenous infusion may be terminated, i.e.before the total recommended dose has been administered. Intravenous use of verapamil hydrochloride may be accompanied by a hypotensive response which can be precipitous, by a rapid ventricular rate, extreme bradycardia or asystole.


An intravenous preparation of calcium chloride or calcium gluconate should be available in the event of any adverse hemodynamic phenomenon. Concomitant use of beta-blockers is contraindicated.

The recommended doses of Verapamil Hydrochloride Injection USP are as follows:

Adult

Initial Dose: 5 to 10 mg (0.075-0.15 mg/kg) may be given as an intravenous bolus over at least 2 minutes.

Repeat Dose: 10 mg (0.15 mg/kg) may be injected 30 minutes after the first dose, if the initial response is not adequate. An optimal interval for subsequent intravenous doses has not been determined and should be individualized for each patient.

Elderly Patients: The dose should be administered over at least three minutes to minimize the risk of untoward drug effects.

Children

Initial Dose

0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range 0.75 to 2 mg) should be administered as an intravenous bolus over at least 2 minutes under continuous ECG monitoring.

1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range 2 to 5 mg) should be administered as an intravenous bolus over at least 2 minutes. Do not exceed 5 mg.

Repeat Dose

0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range 0.75 to 2 mg) 30 minutes after the first dose if the initial response is not adequate, under continuous ECG monitoring. An optimal interval for subsequent doses has not been determined, and should be individualized for each patient.

1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range 2 to 5 mg) 30 minutes after the first dose if the initial response is not adequate. An optimal interval for subsequent doses has not been determined, and should be individualized for each patient. Do not exceed 10 mg as a single dose.

Oral therapy with verapamil hydrochloride should replace intravenous therapy as soon as possible, when the physician wishes to continue treatment with verapamil hydrochloride. Duration of treatment will depend on the underlying cause and history of recurrence.


OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre immediately

Symptoms

Based on reports of intentional overdosage of verapamil hydrochloride, the following symptoms have beenobserved: Hypotension (varying from transient to severe), bradycardia to high degree A-V block and sinus arrest, hyperglycemia, stupor and metabolic acidosis. Conduction disturbances seen included: prolongation of A-V conduction time, A-V dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole. Fatalities have occurred as a result of overdose.

Treatment

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions (calcium chloride or calcium gluconate) may increase calcium ion influx across the slow channel.

These pharmacologic interventions have been effectively used in treatment of overdosage with oralverapamil hydrochloride. Clinically significant hypotensive reactions should be treated with vasopressor agents. A-V block is treated with atropine and cardiac pacing. Asystole should be handled by the usualAdvanced Cardiac Life Support measures including the use of beta- adrenergic receptor agonists (e.g.,isoproterenol hydrochloride), other vasopressor agents, or cardiopulmonary resuscitation. Verapamil hydrochloride is not removed by hemodialysis.

Actual treatment and dosage should depend on the severity of the clinical situation and the judgement of thetreating physician. Patients with hypertrophic cardiomyopathy treated with verapamil hydrochloride shouldnot be administered positive inotropic agents marked by asterisks in Table 3).


Table 3. Overdosage Adverse Reactions and Recommended Treatments

Adverse Reaction Proven Effective Treatment Treatment with Good Theoretical Rationale

Supportive Treatment

Shock, cardiacfailure, severehypotension

Calcium salt (IV) (e.g. IV calcium gluconate;

IV metaraminol bitartrate*)

Isoproterenol HCl (IV)

Dopamine (IV)

Norepinephrinebitartrate( (IV)

IV dopamine HCl*;IV dobutamine HCl*

Intravenous fluids; Trendelenburg position

Bradycardia, A-V block, asystole

IV isoproterenol HCl*IV atropine sulphateCardiac pacing

Norepinephrinebitartrate(IV)

Calcium Chloride(IV)

Intravenousfluids (slowdrip)

Rapid ventricular rate(due to antegrade conduction in flutter/fibrillation with WPW or LGLsyndrome)

D.C. cardioversion (high energy may be required)

Procainamide (IV)Lidocaine HCl

(IV)

Intravenousfluids (slowdrip)

* positive inotropic agentDefinition : IV = intravenous


ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Verapamil hydrochloride is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist)that exerts its pharmacological effects by modulating the influx of ionic calcium across the cell membrane ofthe arterial smooth muscle as well as in conducting and contractile myocardial cells.

Verapamil hydrochloride exerts antihypertensive effects by inducing vasodilation and reducing peripheralvascular resistance usually without reflex tachycardia. Verapamil hydrochloride does not blunt hemodynamicresponse to isometric or dynamic exercise.

Verapamil hydrochloride depresses A-V nodal conduction and prolongs functional refractory periods.Verapamil hydrochloride does not alter the normal atrial action potential or intraventricular conduction time,but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibres.

Verapamil hydrochloride may shorten the antegrade effective refractory period of the accessory bypass tract.Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutteror atrial fibrillation and a coexisting accessory A-V pathway following administration of verapamilhydrochloride (see WARNINGS AND PRECAUTIONS, Cardiovascular, Conduction Disturbance).Verapamil hydrochloride has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis.

Verapamil hydrochloride is a potent smooth muscle relaxant with vasodilatory properties, as well as adepressant of myocardial contractility, and these effects are largely independent of autonomic influences.

Compared to baseline, verapamil hydrochloride does not affect electrolytes, glucose, and creatinine. Thehypotensive effect of verapamil hydrochloride is not blunted by an increase in sodium intake.

In hypertensive normolipidemic patients, verapamil hydrochloride had no effects on plasma lipoproteinfractions.

Verapamil's antiarrhythmic effects are believed to be brought about largely by its action on sinus and atrioventricular nodes. Electrical activity in the SA and AV nodes depends, to a significant degree, upon calcium influx through the slow channel. By inhibiting this influx, verapamil slows AV conduction and prolongs the effective refractory period within the AV nodes in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response.

By interrupting re-entry at the AV node, verapamil can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including Wolff-Parkinson-White (W-P-W) syndrome. Verapamil has no effect on conduction across accessory bypass tracts.

Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers.

The vasodilatory effect of verapamil appears to be due to its effect on blockade of calcium channels as well asα-receptors. Verapamil does not induce peripheral arterial spasm.

Verapamil does not alter total serum calcium levels.


Pharmacodynamics

In a study in five healthy males, the S-enantiomer was found to be 8 to 20 times more active than the R-enantiomer in slowing A-V conduction. In another study using septal strips isolated from the left ventricle offive patients with mitral disease, the S-enantiomer was 8 times more potent than the R-enantiomer in reducingmyocardial contractility.

Pharmacokinetics

Distribution

Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8to 6.8 L/kg in healthy subjects. R-verapamil is 94% bound to plasma albumin, while S-verapamil is 88%bound. In addition, R-verapamil is 92% and S-verapamil 86% bound to alpha-1 acid glycoprotein.

Verapamil hydrochloride crosses the placental barrier and can be detected in umbilical vein blood atdelivery. Verapamil hydrochloride is excreted in human milk.

Metabolism

In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism by thecytochrome P-450 system in the liver. The particular isoenzymes involved are CYP3A4, CYP1A2, andCYP2C family. Thirteen metabolites have been identified in urine, most in only trace amounts. The majormetabolites have been identified as various N- and O-dealkylated products of verapamil. Norverapamil canreach steady-state plasma concentrations approximately equal to those of verapamil itself. Thecardiovascular activity of norverapamil appears to be approximately 20% that of verapamil, which wasobserved in a study in dogs. The degree of biotransformation during the first pass of verapamilhydrochloride may vary according to the status of the liver in different patient populations. In patients withhepatic insufficiency, metabolism is delayed and elimination t½ prolonged up to 14 to 16 hours.

The onset of action of a single intravenous injection is usually 1-2 minutes, with peak effect occurringbetween 3-5 minutes and virtual dissipation of the hemodynamic effects between 10-20 minutes. Verapamil isabsorbed rapidly. From a comparison of the areas under the time concentration curves of total plasmaradioactivity, following oral and IV administration, as well as based on cumulative urinary excretion,absorption has been calculated at 90 to 92%. The absolute bioavailability of unchanged verapamil is about 10to 20% because of an intense first-pass metabolism.

The elimination of unchanged substance from plasma after intravenous administration occurs with a half-lifebetween 3.5 and 7.4 hours. Total radioactivity, however, is eliminated with a half-life of about24 hours.

The binding of verapamil to plasma protein is about 90%. Sixty-three to 70% of a radioactive dose waseliminated in the urine after oral as well as intravenous administration, and up to 16% was excreted in the feces.

Verapamil undergoes extensive and variable hepatic metabolism by the cytochrome P450 system. Theparticular isoenzymes involved are CYP 3A4, CYP 1A2 and the CYP 2C family.


Excretion

Approximately 50% of an administered dose of verapamil is eliminated renally within 24 hours, 70% withinfive days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of an administered dose is excretedrenally as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow,approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Influence of Food

Administration of verapamil hydrochloride with food results in marked prolongation of Tmax (45 to 75%)

and slight decreases in Cmax (about 15%) and AUC (1 to 8%). Food thus produces a slight decrease inbioavailability (AUC), but a narrower peak-to-trough ratio.

Hemodynamics

Verapamil reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolus injection.

The commonly used intravenous doses of 5 - 10 mg verapamil produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased.

Special Populations and Conditions

GeriatricsThe pharmacokinetics of verapamil hydrochloride are significantly different in elderly (≥ 65 years), comparedto younger subjects. AUCs are increased approximately 80% with verapamil hydrochloride. In the elderly,verapamil hydrochloride clearance is reduced resulting in increases in elimination t½.

GenderThe effect of gender on verapamil hydrochloride has not been investigated.

RaceThe effect of different races on verapamil hydrochloride, when administered as Verapamil Hydrochloride Injection USP, has not been investigated.

Hepatic InsufficiencyThe degree of biotransformation during the first pass of verapamil hydrochloride may vary according to the status of the liver in different patient populations. In patients with hepatic insufficiency, verapamil hydrochloride clearance is reduced by 30% and elimination t½ prolonged up to 14 to 16 hours (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION).


Renal Insufficiency

About 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the urine. In onestudy in healthy volunteers, the total body clearance after intravenous administration of verapamilhydrochloride was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil hydrochloride in patientswith renal disease is decreased. In two studies with oral verapamil hydrochloride, no difference inpharmacokinetics could be demonstrated (see WARNINGS AND PRECAUTIONS, Renal, Renal Insufficiency). Verapamil hydrochloride and norverapamil are not removed by hemodialysis.

Genetic Polymorphism

The effect of genetic polymorphism on verapamil hydrochloride pharmacokinetics has not been investigated.

STORAGE AND STABILITY

Store between 20 C and 25C. Protect from light and freezing. Retain in carton until ready for use. For single use only. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Verapamil Hydrochloride Injection USP is supplied in single dose containers as follows:

- 2.5 mg/mL in 2 mL (5 mg/2 mL,) ampoules, sleeves of 10, List 4011.

- 2.5 mg/mL in 2 mL (5 mg/2 mL,) fliptop vials, cartons of 5, List 1144.

Composition:

Verapamil Hydrochloride Injection USP is a sterile, nonpyrogenic solution containing verapamil

hydrochloride 2.5 mg/mL (equivalent to 2.3 mg/mL verapamil) and sodium chloride 8.5 mg/mL in water for

injection. The solution contains no bacteriostat or antimicrobial agent and is intended for single use only.

May contain hydrochloric acid for pH adjustment; pH 4.9 (4.0 to 6.5).

SPECIAL HANDLING INSTRUCTIONS

Any unused portion should be discarded immediately.

Verapamil Hydrochloride Injection USP should be inspected visually for particulate matter and

discolouration prior to administration. Use only if solution is clear.


PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Verapamil Hydrochloride

Chemical Name: Benzeneacetonitrile,α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-methylamino]propyl]-3,4 -dimethoxy-α-(1-methylethyl) hydrochloride

Structural Formula:

Molecular Formula: C27H38N2O4 . HCl

Molecular Weight: 491.07

Description:

Verapamil hydrochloride occurs as a white or almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water; freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble in ether.

It has a pH between 4.5 and 6.5 and a melting range between 140 and 144C.


DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

Verapamil hydrochloride was initially investigated in experimental animals as a smooth muscle relaxant,with vasodilator properties. Subsequent studies have demonstrated that verapamil hydrochloride hassignificant antiarrhythmic effects when tested in a variety of experimental arrhythmias. The mechanism ofaction of verapamil hydrochloride seems to be the blocking of transmembrane influx of calcium throughthe slow channels, without affecting to any significant degree, transmembrane influx of sodium throughthe fast channels. It does not directly modify calcium uptake, binding or exchange by cardiac microsomes.Its main locus of action seems to be the superficially located membrane storage sites for calcium.

In isolated cardiac tissues, at low to moderate concentrations, verapamil exerts little or no effect on actionpotential amplitude, but suppresses activity in the sinoatrial (S-A) and atrioventricular (A-V) nodes. Anyactivity within the S-A and A-V nodes seems to be particularly sensitive to the suppressant effects ofverapamil because normal impulse formation in the sinus node and conduction in the A-V node appear to bemaintained by operation of slow channel mechanisms. The depressant effects exerted by verapamil on A-Vnodal conduction may in part explain its effectiveness in treating supraventricular tachycardia.

Verapamil has a marked negative inotropic effect on isolated cardiac muscle. In intact animals, thedepressant effect on cardiac output and stroke volume is dose-dependent.

Although verapamil has local anaesthetic properties, in clinically relevant doses it does not affect the rate ofeither the depolarization or the repolarization phase of the cardiac action potential. Verapamil does not havebeta-blocking properties, although it antagonizes beta-adrenergic influences on the heart by a functionalantagonism, due to its basic pharmacodynamic properties at the level of the conduction system and themyocardium.

In animal studies, the S-enantiomer has 15 and 50 times the activity of the R-enantiomer in reducingmyocardial contractility in isolated blood-perfused dog papillary muscle and isolated rabbit papillarymuscle, respectively, and twice the effect in reducing peripheral resistance.


TOXICOLOGY

Acute Toxicity

Table 4. Lethal Dose 50 (LD50) (mg/kg) of Verapamil

Intravenous Intraperitoneal Subcutaneous Oral

Rat 16 67 107 114

Mouse 8 68 68 163

Guinea Pig - - - 140

Juvenile Rat - - - 93 (M)

- - - 113 (F)

Juvenile Rabbit - - - 114.2 (M)

- - - 129.8 (F)

Definitions:M = male; F = female

Symptoms preceding death were similar in both sexes with marked sedation, decreased excitability, forcedrespirations, clonic spasms and convulsions.

Subacute Toxicity

Oral Studies

Verapamil was administered orally in doses of 12.5, 25 and 50 mg/kg per day, to rats via food for 14 weeks(29 animals/group) and to dogs for 6 days/week in capsules, for 15 to 16 weeks (4 animals/ group). Baboonsreceived 2, 4, 8, 16, 32 and 64 mg/kg by mouth daily for 4 weeks(2 animals/group).

In rats, a dose-related increase in heart and lung weights was found. Dogs given 25 to 50 mg/kg showedslight weight loss and a significant reduction in heart rate up to week 11, followed by a gradual return tonormal. In one dog on 12.5 mg/kg, one on 25 mg/kg and in all animals on 50 mg/kg, there was emesis duringthe first two weeks of the study. Serum glutamic-pyruvic transaminase (SGPT) was elevated for one dog on25 mg/kg at week 9 and for two animals on 50 mg/kg at the end of the test. Macroscopic examinations atnecropsy were negative and there were no drug-attributed histological changes. The baboons showed no drug-related changes.

Intramuscular Studies

Beagle dogs were given 0, 2 and 10 mg/kg, 5 days/week for 30 days (4 animals/group). Injection sites in allanimals became edematous and a dose-related reduction in heart rate was observed. At 10 mg/kg, hemoglobinand hematocrit values decreased and one animal had a raised SGPT. At necropsy, edema was noted atinjection sites and higher spleen weights were recorded at the 10 mg/kg dose. One dog on this dose alsoshowed increased inflammatory cell infiltration in the liver, with some hepatic cell degenerative changes.


Intravenous Studies

Verapamil was given to Sprague-Dawley rats at 0.2, 1.0 and 5.0 mg/kg once daily for 4 weeks (30animals/group) and similarly to beagle dogs at 0.1, 0.4 and 1.6 mg/kg levels (6 animals/group).

At the highest dose level, all dogs showed some restlessness, salivation and laboured breathing, along withdelayed A-V conduction in one-half of the animals. In 4 of 6 animals at the highest dose (1.6 mg/kg),sporadic small focal gatherings of Kupffer cells, with death of individual liver cells (necrobioses and/ornecrosis of hepatocytes), were found histopathologically.

Chronic Toxicity

Oral

Rats were given verapamil at 10, 15, 25, 30, 60 and 62.5 mg/kg/day (50 animals/group) and beagle dogs at10, 15, 25, 30, 40, 60, 62.5, 70, 81 and 85 mg/kg (6 animals/group) for 12 and 18 months. Clinical signswere observed and changes in food consumption, consistency of stools, hemograms, clinical chemistry andurinalyses performed. Blood pressure, electrocardiogram (ECG) and ophthalmoscopic examinations weredone on the dogs.

In one 18-month rat study, an increase in weight of the thyroid glands in females on the 62.5 mg/kg dosewas noted. In a later 12-month study, a slight reduction in weight gain was recorded.

In dogs, at doses of 60 mg/kg and greater, toxic signs such as vomiting, salivation, reversible hyperplasiaof the gums, reduced food consumption, slight weight loss and a transitory, slight to moderate elevation ofSGPT were noted and three of the animals died. The 40 mg/kg dose caused loss of coat colour and hair,and a delay in A-V conduction.

In another study, atypical lens changes (cataracts) were observed in eight beagles receiving toxic doselevels (62.5 and 70 mg/kg). In a later study, four beagles were given 81 mg/kg for 18 months and nonedeveloped cataracts. It was concluded that any changes caused by verapamil in lens transparency arespecific to the beagle. This is supported by the absence of similar lesions in other species studied, and bythe apparent lack of any impairment by verapamil of carbohydrate or energy metabolism in lenticulartissue. The water-soluble proteins of the canine lens are known to have differences from those in otherspecies.

Mutagenicity and Carcinogenicity

Mutagenicity

In vitro mutagenicity tests showed that verapamil did not have mutagenic properties in five different strainsof Salmonella typhimurium, nor in studies on chromosomal aberrations and sister chromatid exchanges(SCE) in human lymphocytes, nor in the hypoxanthine guanine phosphoribosyltransferase (HGPRT)-testwith V-79 Chinese hamster cells, and also not in the cell transformation assay with Syrian hamster embryocells. In addition, verapamil did not show any SCE-inducing activity in vivo (Chinese hamster).

Carcinogenicity

In a 24-month carcinogenicity study, verapamil hydrochloride was administered orally to 50 male and 50female rats in the diet as actual mean doses of 9.3/9.5, 32.6/33.2, and 112.2/102.5 mg/kg/day, respectively.


Two hundred animals served as controls.

Drug-related significant reductions in body weight and mortality were seen in males and females of the highdose group.

Dose-related cardiac lesions (dilatation, atrial thrombi and myocardial metaplasia, combined withhydrothorax) were seen in the high dose group. These cardiac lesions are considered related to a chronic,exaggerated pharmacologic effect at this high dose level.

At the end of the study, all rats were examined histopathologically with regards to tumorigenesis. All non-neoplastic and neoplastic lesions were considered to reflect the spectrum of spontaneous lesions commonlyencountered in rats of this age and strain. As compared to the controls, the type and incidence of theselesions were not increased in treated rats.

IrritationTwo concentrations of verapamil, 10 mg/mL in a 1 mL dose and 50 mg/mL in 0.25, 0.5 and 1 mL dose wereinjected intramuscularly into 5 albino rabbits, with each animal receiving the 4 doses once. Gross signs ofirritation consisted mainly of congestion at the injection sites, with no evidence of necrosis or otherdegenerative changes.

In another study, verapamil was examined in mongrel dogs for local tolerance after single intravenous,intramuscular, paravenous and intra-arterial administration of about 5 mg/animal. Sites of injection werechecked daily for manifestations of inflammation and sensitivity to pressure. Later, several tissue specimenswere taken from the respective injection sites and examined histologically. The intravenous injection ofverapamil caused no irritation. After intramuscular, paravenous and intra-arterial administration changesobserved were mild inflammation or slight degenerative alterations in muscle cells. These were reversible.

Reproduction and Teratology

Studies were carried out in rats and rabbits with verapamil given in food and/or by gastric tube. Thesestudies included fertility and general reproduction performance in rats, teratogenicity studies in rats andrabbits and peri- and post-natal studies in rats. Rats were given 2.5, 12.5, 25 and 100 mg/kg body weight, bygastric tube and 1.3, 1.6, 5.2, 7.5, 13.3, 16 and 55 mg/kg body weight in food. In another teratogenicitystudy, rats were given 5, 10 and 20 mg/kg body weight by gavage three times daily at an interval of about4.5 hours. Rabbits were given 5 and 15 mg/kg body weight by gastric tube.

There was no evidence of teratogenicity in either species and no embryotoxic effects observed in the ratsdosed via food, or with doses up to 12.5 mg/kg body weight given by gastric tube, or with doses up to 10mg/kg three times a day. The single daily dose of 25 mg/kg body weight or more, caused a higher resorptionrate in the rat. The dose of 20 mg/kg three times a day was embryocidal and retarded fetal growth anddevelopment, probably because of adverse maternal effects reflected in reduced weight gains of the dams.This oral dose has also been shown to cause hypotension in rats. There was no difference in resorption ratesobserved in the rabbit and no effect on peri- and post-natal development or fertility in the rat.


REFERENCES

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2. American Hospital Formulary Service (AHFS) Drug Information 93. American Society ofHospital Pharmacists Inc., Ed. McEvoy GK, 1993.

3. Bauer LA, et al. Verapamil Inhibits Ethanol Elimination and Prolongs the Perception of Intoxication.Clin Pharmacol Ther 1992; 52(1):6-10.

4. Benaim ME. Asystole after verapamil. Br. Med. J. April 15, 1972:169.

5. Bonow RO, Leon MB, Rosing DR, et al. Effects of Verapamil and Propranolol on Left VentricularSystolic Function and Diastolic Filling in Patients with Coronary Artery Disease: RadionuclideAngiographic Studies at Rest and During Exercise. Circulation 1981; 65:1337-50.

6. Carrasco HA, Fuenmeyer A, Barboza JS and Gonzales G. Effect of verapamil on normalsinoatrial node function and on sick sinus syndrome. Am. Heart J. 1978, 96(6):760-771.

7. Compendium of Pharmaceuticals and Specialties, Ed: Schnell Br. et al. 1993.

8. Cubeddu LX, Aranda J, Singh B, et al. A Comparison of Verapamil and Propranolol for the InitialTreatment of Hypertension - Racial Differences in Response. J Am Med Assoc l986; 256:2214-21.

9. De Silva OA, De Melo RA and Filho JPJ. Verapamil acute self-poisoning. Clin. Tox. 1979,14(4):361-367.

10. Dominic JA, Bourne DWA, Tan TG, Kirsten EB, McAllister, RG. Pharmacology of Verapamil. III. Pharmacokinetics in normal subjects after i.v. drug administration. J Cardio Pharmacol 1981;3:25-38.

11. Eichelbaum M, Mikus G, Vogelgensang B. Pharmacokinetics of (+), (-) and (+) verapamil after i.v. administration. Br J Clin Pharmacol 1984;17:453-458.

12. Ferlinz J, Easthope JL. Effects of Verapamil on Myocardial Performance in Coronary Disease.Circulation 1979; 59:313-9.

13. Ferlinz J, Turbow ME, Aronow WS. Myocardial Metabolism and Anginal Threshold in CoronaryDisease after Verapamil Administration. Clin Invest Med 1980; 3:101-9.

14. Follath F, Fromer M, Meier P, Vozeh S. Pharmacodynamic Comparison of Oral and Intravenous

Verapamil in Atrial Fibrillation. Clin Invest Med 1980; 3:49-52.

15. Frishman WH, Klein NA, Klein P, et al. Comparison of Oral Propranolol and Verapamil for CombinedSystemic Hypertension and Angina Pectoris. A Placebo-controlled Double-blind RandomizedCrossover Trial. Amer J Cardiol 1982; 50:1164-1172.

16. Frishman WH, Klein NA, Strom JA, et al. Superiority of Verapamil to Propranolol in Stable AnginaPectoris: A Double-blind, Randomized Crossover Trial. Circulation 1982; 65(suppl.I):I51-9.


17. Fuhr U, Woodcock BG and Siewert M. Verapamil and drug metabolism by the cytochrome P450 isoform CYP1A2. 1992, 42: 463-464.

18. Gigante M, Toffoli G and Boiocchi M. Pharmacokinetics of doxorubicin coadministered with high-dose verapamil. British Journal of Cancer, 1995, 71:134-136.

19. Gould BA, Mann S, Kieso H, Balasubramanian V, Raftery EB. The Role of a Slow Channel Inhibitor,Verapamil, in the Management of Hypertension. Clin Exp Pharmacol Physiol 1982; Suppl 6:113-121

20. Isoptin. Summary basis for approval. FDA Document. 1981.

21. Johnson SM, Mauritson DR, Corbett JR, Woodward W, Willerson JT, Hillis LD. Double- blind,Randomized, Placebo-controlled Comparison of Propranolol and Verapamil in the Treatment ofPatients with Stable Angina Pectoris. Am J Med 1981; 71:443-51.

22. Johnson SM, Mauritson DR, Willerson JT, Hillis LD. A Controlled Trial of Verapamil for Prinzmetal's Variant Angina. New Eng J Med 1981; 304:862-6.

23. Kaltenbach M, Hopf R, Kober G, Bussmann WD, Keller M, Petersen Y. Treatment of HypertrophicObstructive Cardiomyopathy by Verapamil. Br Heart J 1979; 42:35-42.

24. Keefe DL, Yee YG, Kates RE. Verapamil protein binding in patients and normal subjects. Clin Pharmacol Ther 1981; 29(1):21-26.

25. Klein HO, Kaplinsky E. Digitalis and Verapamil in atrial fibrillation and flutter: is verapamil now the preferred agent? Drugs 1986; 31:185-197.

26. Klein HO, Lang R, Weiss E, et al. The Influence of Verapamil in Serum Digoxin Concentrations.Circulation 1982; 65:998-1003.

27. Kroemer HJ, Gautier J-C, Beaune P, Henderson C, Wolf CR and Eichelbaum M. Identification of P450enzymes involved in metabolism of verapamil in humans. Naunyn-Schmiedeberg's Arch Pharmacol1993, 348:332-337.

28. Kuhlmann J, Marcin S. Effects of verapamil on pharmacokinetics and pharmacodynamics of digitoxin in patients. Am Heart J 1985; 110:1245-1249.

29. Kumar GN, Walle UK and Walle T. Cytochrome P450 3A-mediated human liver microsomal taxol6�-hydroxylation. J. Pharm. and Exp. Ther., 1994, 268(3): 1160-1165.

30. Leitner RP, Hawker RE, Celermajer JM. Intravenous verapamil in the treatment of paroxysmal supraventricular tachycardia in children. Aust Pediatr J 1983;19:40-44.

31. Massumi RA, Martin J, Udhoji H. Verapamil in parasystolic ventricular tachycardia and other wide QRS rhythms. Am Heart J 1986;111:400-405.

32. McGovern B, Garan H, Ruskin JN. Precipitation of cardiac arrest by verapamil in patients with Wolff-Parkinson White-Syndrome. Ann Int Med 1986; 104:791-794.

33. Miller MR, Withers R, Bhamra R, Holt DW. Verapamil and Breast-feeding. Eur J Clin Pharmacol,1986; 30:125-6.


34. Nayler WG. Cardioprotective Effects of Calcium Ion Antagonists in Myocardial Ischemia.Clin Invest Med 1980; 3:91-9.

35. Nayler WG and Szeto J. Effect of verapamil on contractility, oxygen utilization and calciumexchangeability in mammalian heart muscle. Cardiovascular Res. 1972, 6:120-128.

36. Packer M, Meller J, Medina N, et al. Hemodynamic Consequences of Combined Beta- adrenergic andSlow Calcium Channel Blockade in Man. Circulation 1982; 65:660-8.

37. Perez-Reyes M, et al. Interaction Between Ethanol and Calcium Channel Blockers in Humans.Alcohol Clin Exp Res 1992;16(4):769-775.

38. Perkins CM. Serious verapamil poisoning. Treatment with intravenous calcium gluconate. Br. Med. J.October 21, 1978: 1127 and 1574.

39. Porter CJ, Garson A, Gillette PC. Verapamil: an effective calcium blocking agent for pediatric patients. Pediatrics 1983;71:748-55.

40. Pozenel H. Plasma Concentration and Blood Pressure Effect of a Sustained Release VerapamilPreparation. In Calcium Antagonists & Hypertension Current Status, Excerpta Medica, Amsterdam,1986, pp 56-65.

41. Rinkenberger RL, Prystowsky EN, Heger JJ, Troup PJ, Jackman WM, Zipes DP. Effects of Intravenous and Chronic Oral Verapamil Administration in Patients with SupraventricularTachyarrhythmias. Circulation 1980; 62:996-1010.

42. Rosing DR, Condit JR, Maron BJ, et al. Verapamil Therapy: A New Approach to the PharmacologicTreatment of Hypertrophic Cardiomyopathy: III. Effects of Long Term Administration. Am J Cardiol1981; 48:545-553.

43. Royer I, Monsarrat B, Sonnier M, Wright M and Cresteil T. Metabolism of docetaxel by human cytochromes P450: Interactions with paclitaxel and other antineoplastic drugs. Cancer Research,1996, 56:58-65.

44. Schomerus M, Spiegelhalder B, Stieren B and Eichelbaum M. Physiological disposition of verapamil in man. Cardiovascular Res. 1976,10:605-612.

45. Schwartz JB, Keefe DL, Kirsten E, Kates RE, Harrison DC. Prolongation of Verapamil EliminationKinetics During Chronic Oral Administration. Am Heart J 1982; 104:198-203.

46. Singh BN, Ellrodt G and Peter T. Verapamil: a review of its pharmacological properties andtherapeutic use. Drugs 1978, 15:169-197.

47. Subramanian VB, Bowles MJ, Khurmi NS, Davies AB, Raferty EB. Randomized Double- blindComparison of Verapamil and Nifedipine in Chronic Stable Angina. Am J Cardiol 1982; 50:696-703.

48. Sung RJ, Elser B and McAllister, R.G. Intravenous verapamil for termination of reentrantsupraventricular tachycardia. Ann. Int. Med. 1980, 93:682-689.


49. Sung RJ, Waxman HL, Elser B, Juma Z. Treatment of paroxysmal supraventricular tachycardia and atrial flutter-fibrillation with i.v. verapamil. Efficacy and mechanism of action. Clin Inv Med 1980;3:41-47.

50. Vaughan-Neil EF, Snell NJC and Bevan G. Hypotension after verapamil. Br. Med. J. May 27,1972:529.

51. Vincenzi M, Allegri P, Gabaldo S, Maiolino P and Ometto R. Hemodynamic effects caused by IV administration of verapamil. Drug Res. 1976, 26(6):1221-1223.

52. Vohra J. Verapamil in cardiac arrhythmias: an overview. Clin Exp Pharmacol Physiol 1982;Supp 6:129-134.

53. Vohra J, Ross D, Cole P, Hunt D, Sloman G. The Effect of Orally Administered Verapamil onAtrioventricular Nodal Conduction and Refractoriness. I.R.C.S., Med Sci 1980; 8:45.

54. Waxman HL, Myerburg RJ, Appel R, Sung RJ. Verapamil for control of ventricular rate in paroxysmal supraventricular tachycardia and atrial fibrillation or flutter. Ann Intern Med 1981;94:1-6.

55. Weiss AT, Lewis BS, Halon DA, Hasin Y, Gotsman MS. The use of calcium with verapamil in the management of supraventricular tachyarrhythmias. Inter J Cardiol 1983;4:275-280.

56. Wit AL and Cranefield PF. Effect of verapamil on the sinoatrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant atrioventricular nodal tachycardia. Cir. Res. 1974, 35:413-425.

57. Woodcock BG, Reitbrock I, Vohringer HF, Rietbrock N. Verapamil disposition in liver disease and intensive-care patients: kinetics, clearance, and apparent blood flow relationships. Clin Pharmacol Ther 1981; 29:27-34.

58. Zachariah PK, Sheps SG, Schirger A, Spiekerman RE, O'Brien PC, Simpson KK. Verapamil& 24-hour Ambulatory Blood Pressure Monitoring in Essential Hypertension. Am J Cardiol 1986;57:74D-79D.

59. Zacny JP, Yajnik S. Effects of Calcium Channel Inhibitors on Ethanol Effects and Pharmacokinetics inHealthy Volunteers. Alcohol 1993;10(6):505-509.

60. Product Monograph Verapamil Hydrochloride Injection USP, Sandoz Canada Inc., Submission Control No. 242315, December 29, 2020.

61. Product Monograph ISOPTIN SR, BGP Pharma ULC, Submission Control No 236383; May 26, 2020.

IMPORTANT: PLEASE READ


PART III: CONSUMER INFORMATION

PrVerapamil Hydrochloride Injection USP 2.5 mg/mL

Sterile Solution

This leaflet is PART III of a three-part “ProductMonograph" published when Verapamil Hydrochloride Injection USP was approved for sale in Canada and is designed specifically for consumers. This leaflet is a summary and will nottell you everything about Verapamil HydrochlorideInjection USP. Contact your doctor or pharmacistif you have any questions about the drug.

ABOUT THIS MEDICATION

Verapamil Hydrochloride Injection USP is used tocontrol life threatening:

Abnormal heart rhythms Rapid heartbeat

What it does:Verapamil Hydrochloride Injection USP is a calciumchannel blocker. Calcium channel blockers change theamount of calcium getting into the muscle cells of yourheart and blood vessels. This can change the strength andspeed at which your heart beats. It also opens up theblood vessels so that blood can be pumped around yourbody more easily. This helps to lower your bloodpressure.

When it should not be used:Verapamil Hydrochloride Injection USP should not beused if: you are allergic to any component of Verapamil

Hydrochloride Injection USP (see What thenonmedicinal ingredients are).

you have had a heart attack you have heart failure you have serious heart or circulation problems you have a slow or irregular heartbeat. you have very low blood pressure or feel faint when

you get up. you are breast-feeding while taking this medication. you have serious heart disease and are taking beta

blockers. You can recognize beta blockers because their medicinal ingredient ends in ‘-lol’.

you are taking ivabradine, a drug that lowers yourheart rate

you are taking flibanserin, a medicine to treat generalized hypoactive sexual desire disorder. You must wait at least 2 weeks after your last dose of Verapamil Hydrochloride Injection USP before starting flibanserin. You must wait at least 2 days

after your last dose of flibanserin before starting Verapamil Hydrochloride Injection USP.

What the medicinal ingredient is:Each mL contains 2.5 mg verapamil hydrochloride

What the non-medicinal ingredients are:Each mL contains sodium chloride, hydrochloric acid and water for injection

What dosage forms it comes in:Verapamil Hydrochloride Injection USP is available in 2.5 mg/mL in 2 mL (5 mg/2 mL,) ampoules, sleeves of 10, and 2.5 mg/mL in 2 mL (5 mg/2 mL,) fliptop vials, cartons of 5

LATEX-FREE STOPPER: Stopper contains no drynatural rubber.

WARNINGS AND PRECAUTIONS

BEFORE Verapamil Hydrochloride Injection USP isused, tell your doctor if: you have heart failure you have low blood pressure and slow heart rate you have kidney disease. you have liver disease. you are taking beta-blocker to treat high blood

pressure, angina and heart failure. you have a neuromuscular disease (i.e. myasthenia

gravis or Duchenne muscular dystrophy). you are pregnant or planning to become pregnant you are breast-feeding you are under 18 years of age you are 65 years of age or older you are taking any other medications

INTERACTIONS WITH THIS MEDICATION

As with most medicines, interactions with other drugs are possible. Tell your doctor if you are taking or have recently taken any other medications, including non-prescription medicines, vitamins,minerals, natural supplements, or alternativemedicines.

Additional monitoring of your dose or condition maybe needed if you are taking other drugs.

The following may interact with VerapamilHydrochloride Injection USP: Anti-anxiety drugs, including busprione and

midazolam Antibiotics such as clarithromycin,



erythromycin, telithromycin, rifampicin, Dabigatran, rivaroxaban, apixaban, and edoxaban

(blood thinners) Anti-diabetic medications, e.g. glyburide Anti-epilepsy drugs (e.g. carbamazepine,

phenytoin, phenobarbital) Asthma medications e.g. theophylline, Blood pressure lowering drugs, including alpha

blockers (e.g. prazosin, terazosin); beta-blockers(e.g. propranolol, metoprolol, atenolol); diuretics(e.g. hydrochlorothiazide);

Cholesterol lowering medications (e.g.simvastatin, atorvastatin, lovastatin);

Dantrolene , used for severe muscle spasms or severefever

Doxorubicin, a cancer medication Drugs that affect your immune system (e.g.

cyclosporine, sirolimus, tacrolimus,everolimus);

Drugs used to control heart rate (e.g. amiodarone,digoxindisopyramide, flecainide, lidocaine, quinidine);

Cimetidine, an ulcer medication Gout medications including colchicine,

sulfinpyrazone Imipramine, an antidepressant Lithium for the treatment of bipolar disease Migraine medication, e.g. almotriptan, Nitrous oxide and other inhalation anesthetics Nonsteroidal anti-inflammatory drugs (NSAIDs),

used to reduce pain and swelling. e.g.acetylsalicylic acid, ibuprofen, naproxen, andcelecoxib.

Neuromuscular blocking agents (e.g. atracurium); HIV-anti-viral medication (e.g. ritonavir); Grapefruit juice; Alcohol; St John’s Wort. Ivabradine (a drug that lowers your heart rate).

Please check with your doctor before taking any othermedications with Verapamil Hydrochloride Injection USP.

PROPER USE OF THIS MEDICATION

Verapamil hydrochloride Injection USP will beadministered by a healthcare professional

Usual dose :AdultInitial Dose: 5 to 10 mg (0.075 to 0.15 mg/kg bodyweight) given as an IV bolus over at least 2 minutes.

Repeat Dose: 10 mg (0.15 mg/kg body weight) 30

minutes after the first dose if the initial response is notadequate. An optimal interval for subsequent IV doseshas not been determined, and should be individualizedfor each patient.

Older Patients (65 years or older):The dose should be administered over at least 3 minutesto minimize the risk of untoward drug effects.

Children

Initial Dose:0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual singledose range 0.75 to 2 mg) should be administered as anIV bolus over at least 2 minutes under continuous ECGmonitoring.

1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual singledose range 2 to 5 mg) should be administered as an IVbolus over at least 2 minutes. Do not exceed 5 mg.

Repeat Dose:0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual singledose range 0.75 to 2 mg) 30 minutes after the first doseif the initial response is not adequate (under continuousECG monitoring). An optimal interval for subsequentdoses has not been determined, and should beindividualized for each patient.1 to 15 years: 0.1 to 0.3 mg/kg body weight (usualsingle dose range 2 to 5 mg) 30 minutes after the firstdose if the initial response is not adequate. An optimalinterval for subsequent doses has not beendetermined, and should be individualized for eachpatient. Do not exceed 10 mg as a single dose.

Oral treatment should replace intravenous therapy assoon as possible, when the physician wishes tocontinue treatment with verapamil hydrochloride.Duration of treatment will depend on the underlyingcause and history of recurrence.

Overdose:In case of drug overdose, contact a health carepractitioner, hospital emergency department or regional Poison Control Centre immediately,even if there are no symptoms.

Missed dose:Your healthcare professional will ensure that thisproduct is administered properly and doses are notmissed.

SIDE EFFECTS AND WHAT TO DO ABOUT



THEM

Side effects may include: constipation, headache nausea unusual tiredness or weakness

If any of these affects you severely, tell your doctor,nurse or pharmacist.

SERIOUS SIDE EFFECTS, HOW OFTEN THEYHAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect Talk to your healthcare professional

Stoptaking

drug andget

immediatemedical

help

Onlyifsevere

In allcases

Com

mon

Low bloodpressure:dizziness, fainting,lightheadedness.May occur whenyou go from lyingor sitting tostanding up

√

Fast, slow orirregular heartbeat

√

Difficultybreathing,coughing orwheezing

√

Swelling in thearms, legs, anklesor feet

√

SERIOUS SIDE EFFECTS, HOW OFTEN THEYHAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect Talk to your healthcare professional

Stoptaking

drug andget

immediatemedical

help

Onlyifsevere

In allcases

Un

com

mon

Angioedema andSevere AllergicReaction(anaphylaxis):swelling of theface, eyes, lips,tongue or throat,difficultyswallowing orbreathing, nauseaor vomiting,wheezing, rash,hives itching,fever, abdominalcramps, chestdiscomfort ortightness

√

Muscle weakness √

Seizures √

This is not a complete list of side effects. For any unexpected effects while taking Verapamil Hydrochloride Injection USP, contact your doctor or pharmacist.

HOW TO STORE IT

Store between 20 C and 25C. Protect from light and freezing

Reporting Side EffectsYou can report any suspected side effects associatedwith the use of health products to Health Canada by:

Visiting the Web page on Adverse ReactionReporting (https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada.html)for informationon how to report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada.html





NOTE: Contact your health professional if you needinformation about how to manage your side effects.The Canada Vigilance Program does not providemedical advice.

FOR MORE INFORMATION

NOTE: This CONSUMER INFORMATION leaflet provides you with the most current information at the time of printing.

For the most current information, the ConsumerInformation Leaflet plus the full Product Monograph,prepared for health professionals can be found at:www.pfizer.ca, under Prescription Products, or bycontacting the sponsor, Pfizer Canada ULC at:1-800-463-6001.

This leaflet was prepared by: Pfizer Canada ULCKirkland, QuébecH9J 2M5

Last revised: May 18, 2021

http://www.pfizer.ca/

product monograph verapamil hydrochloride injection usp 2

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